In humans, positive affective states are associated with resilience to depression as well as increased global health and decreased mortality. Currently available antidepressants fail to treat the symptom of decreased positive affect associated with depression. Targeting positive affective states associated with resilience to depression is an attractive alternative treatment approach. Rat hedonic 50-kHz ultrasonic vocalizations (hedonic USVs) are a well established measure of positive affective states. Using this model, we have identified Insulin-like Growth Factor-I as functionally involved in positive- affect-induced resilience to depression. In humans, Insulin-like Growth Factor I (IGFI) has been shown to both increase positive affect and reduce symptoms of depression and anxiety, but peripheral side effects (hypoglycemia) limits its clinical utility. The proposed studies will furthr examine the functional role of IGFI resilience to depression. In these proposed experiments, (i) the optimal brain region for IGFI-induced positive affect and antidepressant effects will be determined, (ii) IGFI-induced resilience will be examined using multiple animal measure of positive affect and depression, and (iii) the therapeutic potential of Insulin-like growth factor binding protein 2 (IGFBP-2) as a treatment for depression will be determined. Studying positive affect and how it relates to resilience to depression is a unique approach that may lead to the creation of novel antidepressants.